Neuroendokrine Tumorerkrankungen Immuntherapie Ulrich Keilholz Charité Comprehensive Cancer Center
effector cell Antigen TCR TCR Antigen Antigen presenting cell Tumor cell Apoptosis Chemotherapy Radiotherapy Necrosis
In all cancer patients, immune-surveillance has failed effector cell Antigen TCR TCR Antigen Antigen presenting cell Tumor cell Apoptosis Chemotherapy Radiotherapy Necrosis
Failure of Immunesurveillance T-cell T- cell Tumor Tumor Tumor Tumor no Antigen no AG-specific blockade of Immunoevasisve T cell response AG-specific Microenvironment T cells
Failure of Immunesurveillance T-cell T- cell Tumor Tumor Tumor Tumor no Antigen no AG-specific blockade of Immunoevasisve T cell response AG-specific Microenvironment T cells
Failure of Immunesurveillance T-cell T- cell Tumor Tumor Tumor Tumor no Antigen no AG-specific blockade of Immunoevasisve T cell response AG-specific Microenvironment T cells
effector cell Stimulation (e.g. Interleukin-2) Antigen TCR TCR Antigen Antigen presenting cell Tumor cell
DTIC, Cisplatin, IFNa with or without intravenous Interleukin-2 in advanced melanoma Study Coordinator: Ulrich Keilholz, Berlin Co-Coordinator: Alexander Eggermont, Rotterdam EORTC trial 18951 J Clin Oncol 2005
100 90 Overall Survival 80 70 60 50 40 30 20 Logrank test: p=0.3142 10 0 0 1 2 3 4 5 6 7 (years) O N Number of patients at risk : 169 180 65 23 11 4 2 0 159 183 60 31 15 6 4 2 Arm A Arm B J Clin Oncol 2005
Failure of Immunesurveillance T-cell T- cell Tumor Tumor Tumor Tumor no Antigen no AG-specific blockade of Immunoevasisve T cell response AG-specific Microenvironment T cells
Vaccine effector cell TCR Antigen Antigen TCR TCR Antigen Antigen presenting cell Tumor cell
T-cell-Targets for immunoregulatory antibodies I Mellman et al. Nature 480, 480-489 (2011)
effector cell CTLA4 CD28 PD1 B7 B7 PD-L1 Antigen presenting cell Tumor cell CTLA4 und PD1: Die zentralen Immune Checkpoints
Anti CTLA4 effector cell CTLA4 CD28 PD1 B7 B7 PD-L1 Antigen presenting cell Tumor cell anti-ctla4 erlaubt Entwicklung von AUTOIMMUNITÄT
effector cell Anti PD1/PDL1 CTLA4 CD28 PD1 B7 B7 PD-L1 Antigen presenting cell Tumor cell anti-pd1 erlaubt EXECUTION der IMMUNITÄT
Melanom
Melanom
RCC
NSCLC
Toxicity Grade CTLA-4 Blockade With Ipilimumab Kinetics of iraes in Melanoma Weber JS, et al. J Clin Oncol. 2012. Time (weeks)
Approximate proportion of patients (%) PD-1 Blockade: Kinetics of iraes in Melanoma 35 30 25 20 15 10 5 0 0 10 20 30 40 Time (weeks) Skin Gastrointestinal Endocrine Hepatic Pulmonary Renal Weber JS, et al. ASCO. 2015.
Change From Baseline in Tumor Size, % Example: Pembrolizumab Antitumor Activity Melanoma 1 (N=655) KEYNOTE-001 100 80 NSCLC 2 (N=262) KEYNOTE-001 H&N 3 (N=132) KEYNOTE-012 Urothelial 4 (N=33) KEYNOTE-012 Gastric 5 (N=39) KEYNOTE-012 60 40 20 0-20 -40-60 -80-100 TNBC 6 (N=32) KEYNOTE-012 chl 7 (N=29) KEYNOTE-013 Mesothelioma 8 (N=25) KEYNOTE-028 Ovarian 9 (N=26) KEYNOTE-028 SCLC 10 (N=20) KEYNOTE-028 Esophageal 11 (N=23) KEYNOTE-028 chl = classical Hodgkin s lymphoma; H&N = head and neck; NSCLC = non-small cell lung cancer; TNBC = triple-negative breast cancer. 1. Daud A 26 et al. 2015 ASCO; 2. Garon EB et al. ESMO 2014; 3. Seiwert T et al. 2015 ASCO; 4. Plimack E et al. 2015 ASCO; 5. Bang YJ et al. 2015 ASCO; 6. Nanda R et al. SABCS 2014; 7. Moskowitz C et al. 2014 ASH Annual Meeting; 8. Alley EA et al. 2015 AACR; 9. Varga A et al. 2015 ASCO; 10. Ott PA et al. 2015 ASCO; 11. Doi T et al. 2015 ASCO.
Change From Baseline in Tumor Size, % Example: Pembrolizumab Antitumor Activity Melanoma 1 (N=655) KEYNOTE-001 100 80 NSCLC 2 (N=262) KEYNOTE-001 H&N 3 (N=132) KEYNOTE-012 Urothelial 4 (N=33) KEYNOTE-012 Gastric 5 (N=39) KEYNOTE-012 60 40 20 0-20 -40-60 -80-100 TNBC 6 (N=32) KEYNOTE-012 chl 7 (N=29) KEYNOTE-013 Mesothelioma 8 (N=25) KEYNOTE-028 Ovarian 9 (N=26) KEYNOTE-028 SCLC 10 (N=20) KEYNOTE-028 Esophageal 11 (N=23) KEYNOTE-028 chl = classical Hodgkin s lymphoma; H&N = head and neck; NSCLC = non-small cell lung cancer; TNBC = triple-negative breast cancer. 1. Daud A 27 et al. 2015 ASCO; 2. Garon EB et al. ESMO 2014; 3. Seiwert T et al. 2015 ASCO; 4. Plimack E et al. 2015 ASCO; 5. Bang YJ et al. 2015 ASCO; 6. Nanda R et al. SABCS 2014; 7. Moskowitz C et al. 2014 ASH Annual Meeting; 8. Alley EA et al. 2015 AACR; 9. Varga A et al. 2015 ASCO; 10. Ott PA et al. 2015 ASCO; 11. Doi T et al. 2015 ASCO.
PD-1 Blockade in Tumors with Mismatch Repair Deficiency Presented By Dung Le at 2015 ASCO Annual Meeting
Mutations per tumor Presented By Dung Le at 2015 ASCO Annual Meeting
Pembrolizumab (anti-pd1) 10 mg/kg alle 2 Wochen Slide 12 Presented By Dung Le at 2015 ASCO Annual Meeting
Slide 13 Presented By Dung Le at 2015 ASCO Annual Meeting
Slide 15 Presented By Dung Le at 2015 ASCO Annual Meeting
Slide 17 Presented By Dung Le at 2015 ASCO Annual Meeting
2WUY1M (BER-04) NET Single Nucleotide Variants (SNVs) 7987 Insertions/Deletions (Indels) 5 10 100 Mutationslast des Tumors Signatur entspricht: C11 alkylating agents (nicht POL eta, da dominant C>T) PI3K-AKT-mTOR Developmental Pathways snv: 2 in NOTCH2, 3 in FBXW7 exp-: NOTCH1, HOXC11 Tyrosine Kinases snv: ERBB3 exp+: RET, ERBB4 exp-: STK11 Hypermutation 7987 nonsilent SNVs, viele nicht in RNA oder mit sehr geringer AF RAF-MEK-ERK snv: NRAS Cell Cycle DNA Damage Response snv: POLE germline rar + zweimal somatic, exp-, MSH2/6, FANCL, ERCC3 exp+: ERCC4/6 exp-: BAP1 Other snv: CDC73 exp+: PDCD1LG2, CD274, CTLA4, viele B- und T-Zell- Gene => Infiltration snv = single nucleotide variant, in = insertion, del = deletion, amp = amplification, exp+ = increased expression exp- = decreased expression, fus = fusion
Konsequenzen Immuntherapie mit Checkpoint-Inhibitoren öffnet komplett neue Perspektiven Saubere Diagnostik nötig, um Wirksamkeit einzuschätzen Einfach Dysfunktions-Mutationen Hohe Mutationslast Starke Inflammation Schwierig Treiber-Mutationen Niedrige Mutationslast Keine Inflammation